One of the main problems associated with cancer chemotherapy is that individual subjects with the same histology do not respond identically to a given agent or a given therapeutic protocol. The response range may vary in large proportions, even in chemosensitive tumors such as breast cancer. A number of determinants of drug sensitivity are well known, such as drug dose, drug combinations and schedule of administration, subject age and status, tumor localization etc, but the intrinsic sensitivity of a given tumor is a major factor in which remains difficult to evaluate.
One strategy to improve the effectiveness of treatment has been to individualize drug treatment as a function of the sensitivity of tumor cells. Methods to predict how effective a drug may be in a subject are typically based on in vitro or ex vivo testing of the tumor cells (taken during a biopsy) to a battery of drugs and chemotherapy agents. Such strategies have several limitations; they are often poor predictors of chemosensitivity in vivo, they are time-consuming, and both manually and cost expensive. The identification of novel cancer subtypes promises to provide more specific, more effective and less toxic therapies. This tumor subset is refractory to commonly used chemotherapeutic agents and therefore is associated with a poor prognosis (Sorlie, et al., 2001, Proc Natl Acad Sci USA 98:10869). To date little progress has been made in identifying specific molecular pathways associated with these refractory cancers that may be effectively targeted for therapeutic purposes.
Human topoisomerase I (topoI) is an essential and ubiquitous enzyme that is involved in various DNA transactions. The identification of topoI as the target of a new class of anti-neoplastic drug (camptothecin, also referred herein as “CPT”) has led to the rapid development of topoI structure-function in the context of cancer therapy. Two CPT analogues, topotecan and irinotecan, are currently used in clinics for small cell lung cancer (SCLC), colon and ovarian cancer and in several refractory cancers, including breast and cervical. However, like most cancer drugs, not all patients respond, in this case only about 30% of patients respond to topoI inhibitors. The topoI protein level is high in most solid tumors, and thus topoI levels can not be used as a predictive marker. Additionally, although topoI is the specific target of CPT, the expression profile of topoI does not provide prognostic index. Based on the preclinical studies, it is likely that clinical resistance to these drugs might be the result of (1) inadequate accumulation of the drug in the tumor, or (2) post-translational modification of topoI. It has been demonstrated that topoI is ubiquitinated and degraded in cells in the response to CPT by ubiquitin proteosomal pathway (UPP). Importantly, the rate of UPP mediated degradation varies in different cancer cells and is correlated to the CPT sensitivity. However the mechanism of ubiquitination dependent proteosomal degradation of topoI in the response to CPT is not understood.
There is a significant need in the art for a satisfactory treatment of tumor subsets refectory or non-responsive to commonly used chemotherapeutic agents, (specifically in epithelial cell cancers such as breast, lung, ovarian, brain, colon and prostate cancers), which overcomes the non-responsiveness exhibited by subjects. Such a treatment could have a dramatic impact on the health of individuals, especially older individuals, among whom cancer is especially common, and females whom have a high incidence of breast cancer.